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Based on exome-sequencing of more than 1,100 patients recruited by the International Parkinson Disease Genomics Consortium, investigators reported that GTP cyclohydrolase-1 deficiency predisposes people to nigrostriatal cell loss, which makes it a novel risk factor for Parkinson's disease.
PHILADELPHIA—Carrying mutations in a gene for an essential enzyme for dopamine production in nigrostriatal cells could increase the risk of developing neurodegenerative Parkinson's disease, researchers said here at the AAN Annual Meeting.
The researchers from London based their conclusions on the results of exome-sequencing of more than 1,100 patients recruited by the International Parkinson Disease Genomics Consortium.
Mutations to the GTP cyclohydrolase-1 (GCH1) gene result in severe reduction of dopamine production in nigrostriatal cells and cause dopa-responsive dystonia (DRD). The disorder appears in childhood, often about the age of 6, as dystonia of the lower limbs. Its first sign is often gait disturbance. The dystonia then spreads, but has an excellent and sustained response to levodopa treatment.
Those affected often have a parent with GCH1-related DRD, or one of the parents might have a GCH1 mutation but not show any symptoms because of incomplete penetrance of the mutation.
Those with these gene mutations might develop adult-onset parkinsonism without dystonia. But the prevailing hypothesis is that this parkinsonism is actually an atypical, age-specific, presentation of DRD — without nigral degeneration.
The researchers wanted to explore the relationship between GCH1 mutations and parkinsonism and whether adult carriers of the gene mutations were at an increased risk of developing Parkinson's disease with neurodegeneration, said Niccolo Mencacci, MD, a clinical research fellow at the University College of London Institute of Neurology. He discussed the findings on behalf of the International Parkinson Disease Genomics Consortium.
The research team first studied four separate families in which pathogenic heterozygous GCH1 mutations were found in individuals with classic DRD and in older family members with no symptoms of DRD but who had adult-onset Parkinson's.
They performed dopaminergic imaging studies with DaTscan, in which a radioactive agent is injected and binds to dopamine transporters in the brain. They found that the values were abnormally reduced in all of the parkinsonian cases, indicating the presence of Parkinson's disease-like dopaminergic nigrostriatal denervation. That suggested that the parkinsonism in mutation carriers was not atypical DRD, after all.
They then turned to the International Parkinson Disease Genomics Consortium database. A total of 1,128 Parkinson's patients, with a mean age at onset of about 47, were matched with 5,935 controls.
Through the exome sequencing, researchers identified 11 different heterozygous GCH1 mutations. Four are known to cause DRD, six were novel mutations, one was a known benign variant.
The frequency of GCH1 mutations was low, but PD patients — in whom mutations were seen in 0.62 percent of cases — were significantly more likely to have mutations than the controls — who had mutations 0.1 percent of the time (p=0.002).
“GCH1 deficiency and the consequent chronic dopamine deficiency could directly predispose [people] to nigral cell death,” Dr. Mencacci suggested.
The study sheds new light on the possible significance of the gene mutations in ways that other studies have failed to show.
He noted that a 1996 study in the Journal of Neurological Sciences concluded that there was no evidence yet that GCH1 mutations were responsible for development of parkinsonism other than in patients with a family history of DRD. But the study included just 29 patients.
Danish investigators reported in a 2006 study of 87 patients in the European Journal of Neurology that they were unable to find a link between GCH1 mutations and early onset PD. And a 2009 study from the Mayo Clinic in the journal Movement Disorders found no evidence in 53 patients that mutations of the gene were associated with early onset of the disease.
“Previous negative studies investigating the contribution of GCH1 variants in small cohorts of PD were underpowered to draw conclusions,” Dr. Mencacci said. These findings now warrant further exploration, he said.
“Further insight into GCH1-associated pathogenetic mechanisms will shed light on the role of dopamine metabolism in nigral degeneration,” Dr. Mencacci said.
Thomas Bird, MD, FAAN, chief of the Division of Neurogenetics at the University of Washington School of Medicine, said this was a “fascinating study that raises many questions about penetrance, expression, and pathogenicity.”
“Why do some persons with a mutation get DRD, others get PD, but nobody gets both?” he asked. “Are the PD cases unusually responsive to levodopa? What is the evidence that the novel mutations are pathogenic?” Dr. Bird serves on the editorial advisory board of Neurology Today.
“This is an interesting observation that adds to the growing list of gene mutations that increase the risk of an individual developing PD,” said Andrew S. Feigin, MD, professor of neurology and molecular medicine at Hofstra North Shore-Long Island Jewish School of Medicine and director of the Laboratory of Experimental Therapeutics for Movement Disorders at the Feinstein Institute for Medical Research. “Though these mutations account for a very small percentage of idiopathic PD cases, this observation might lead to greater insights into the mechanisms underlying neurodegeneration,” said Dr. Feigin, who serves on the editorial advisory board of Neurology Today.
Anthony E. Lang, MD, FAAN, the Lily Safra chair in movement disorders at the University of Toronto, agreed that the findings were “very interesting.”
But he added that the results need further confirmation. “We don't know whether these patients have PD with alpha-synuclein deposition or some other form of parkinsonism. The clinical and pathological findings will be of great interest.”
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